Room‐Temperature Palladium‐Catalyzed Deuterogenolysis of Carbon Oxygen Bonds towards Deuterated Pharmaceuticals

Abstract

Site‐specific incorporation of deuterium into drug molecules to study and improve their biological properties is crucial for drug discovery and development. Herein, we describe a palladium‐catalyzed room‐temperature deuterogenolysis of carbon–oxygen bonds in alcohols and ketones with D2 balloon for practical synthesis of deuterated pharmaceuticals and chemicals with benzyl‐site (sp3 C−H) D‐incorporation. The highlights of this deoxygenative deuteration strategy are mild conditions, broad scope, practicability and high chemoselectivity. To enable the direct use of D2O, electrocatalytic D2O‐splitting is adapted to in situ supply D2 on demand. With this system, the precise incorporation of deuterium in the metabolic position (benzyl‐site) of ibuprofen is demonstrated in a sustainable and practical way with D2O.

Deuterium labelling by electrochemical splitting of heavy water

“…Among the numerous unsaturated bonds, alkynes (C≡C) are the most active in terms of reduction potential and can be readily semi-deuterated to d 2 -alkenes prior to water splitting. The conversion of semi-deuterated alkenes into fully deuterated alkanes is much more challenging due to their shortened bond lengths, which require a more negative potential [39] . The nitro functionality is Modified with permission from ref.…”

“…Substantial efforts have been devoted to regulating the catalytic activity by tailoring the electron structure and state of the d-band center through doping, alloying, defect and strain engineering. For instance, Wu et al [39] reported a phosphorus-doped palladium nanowire (Pd-P) cathode for selective semi-hydrogenation (deuteration) of terminal and internal alkynes using H 2 O(D 2 O) as the H(D) source. The CV pattern in neutral conditions displays a weakened H* adsorption after the addition of alkyne, indicating the competitive coverage of alkyne on the H* ads sites.…”

“…This electrochemical method allows the use of electrons as a green reductant source and can be readily controlled by adjusting external parameters, such as the electrolytes and applied voltages, as well as by materials engineering of the catalyst. This approach has been successfully demonstrated for the reductive deuteration of halides [34][35][36] , alkenes [37,38] , alkynes [39] , unsaturated carboxylic acids [40] and deuterated methylation of nitroarenes, as shown in Figure 2A [41,42] .…”

Nickel-Catalyzed Reductive Deoxygenation of Diverse CO Bond-Bearing Functional Groups

“…Characterization data matched those previously reported. 39 Seeking to further disprove any potential mechanisms involving an alkene intermediate, we synthesized tetradeuterated d4-biphenyl ethanol (65) from bisdeuterated d2-biphenyl acetic acid methyl ester (S20) (prepared according to a literature procedure) 52 and subjected it to the general reaction conditions. We imagined that -if an alkene intermediate were present -then the Ni catalyst could be found on either carbon, leading to deuterium scrambling.…”

“…[1,1'-Biphenyl]-4-d2-acetic acid methyl ester (S20) was prepared from [1,1'biphenyl]-4-glyoxylic acid methyl ester according to a literature procedure. 52 Column chromatography was performed using a gradient of 1→30% ethyl acetate in hexanes to afford (S20) as a colourless liquid (134 mg, 48% yield). Characterization data matched those previously reported.…”